Lack of Evidence for Vaccine‐Associated Enhanced Disease From COVID‐19 Vaccines Among Adults in the Vaccine Safety Datalink

ABSTRACT Purpose Vaccine‐associated enhanced disease (VAED) is a theoretical concern with new vaccines, although trials of authorized vaccines against SARS‐CoV‐2 have not identified markers for VAED. The purpose of this study was to detect any signals for VAED among adults vaccinated against coronavirus disease 2019 (COVID‐19). Methods In this cross‐sectional study, we assessed COVID‐19 severity as a proxy for VAED among 400 adults hospitalized for COVID‐19 from March through October 2021 at eight US healthcare systems. Primary outcomes were admission to an intensive care unit (ICU) and severe illness (score ≥6 on the World Health Organization [WHO] Clinical Progression Scale). We compared the risk of outcomes among those who had completed a COVID‐19 vaccine primary series versus those who were unvaccinated. We incorporated inverse propensity weights for vaccination status in a doubly robust regression model to estimate the causal average treatment effect. Results The causal risk ratio in vaccinated versus unvaccinated was 0.36 (95% confidence interval [CI], 0.15–0.94) for ICU admission and 0.46 (95% CI, 0.25–0.76) for severe illness. Conclusion Among hospitalized patients, reduced disease severity in those vaccinated against COVID‐19 supports the absence of VAED.